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Overcoming acquired immunotherapy resistance in non-small cell lung cancer using ginsenoside Rb1-loaded,
Xiangyuan Jin1, Tanghesi Wuyun2, Yu Zhang2
1Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China.
Abstract:
Non-small cell lung cancer (NSCLC) remains a major global health challenge, with limited therapeutic success due to drug resistance and the immunosuppressive tumor microenvironment (TME). This study explores a novel strategy to overcome acquired resistance to immunotherapy in phosphoinositide 3-kinase (PI3K)-mutated NSCLC. Tumor-derived exosomes (T-exo) were modified with the tumor-targeting peptide TMTP1 and loaded with Ginsenoside Rb1 (Rb1) via electroporation to develop peptide-modified Rb1@T-exo. This innovative delivery system demonstrated enhanced tumor-targeting ability and improved stability and bioavailability of Rb1. Both in vitro and in vivo experiments revealed that Rb1@T-exo effectively suppressed tumor growth and metastasis, significantly inhibited the PI3K/AKT/mTOR signaling pathway, and remodeled the immune microenvironment by promoting M1 macrophage polarization and enhancing CD8+ T cell proliferation and cytotoxicity. Transcriptomic and bioinformatic analyses identified key differentially expressed genes (DEGs) and pathways associated with resistance reversal, including the PI3K/AKT/mTOR and PD-1/PD-L1 pathways. Moreover, Rb1@T-exo synergized with immune checkpoint blockade therapy, demonstrating potential as a dual therapeutic approach. This study highlights the potential of peptide-modified Rb1@T-exo as a targeted therapeutic platform for overcoming immunotherapy resistance in PI3K-mutated NSCLC and provides a promising direction for future anti-tumor therapies.
Insights
This study developed modified exosomes loaded with Ginsenoside Rb1 to overcome immunotherapy resistance in non-small cell lung cancer. The novel treatment suppressed tumor growth and enhanced anti-tumor immunity, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Immunology
- Nanomedicine
Background:
- Non-small cell lung cancer (NSCLC) presents a significant health burden, often exhibiting resistance to immunotherapy due to factors like the tumor microenvironment (TME).
- Acquired resistance to immunotherapy, particularly in PI3K-mutated NSCLC, necessitates novel therapeutic strategies.
Purpose of the Study:
- To develop and evaluate a novel exosome-based drug delivery system for overcoming immunotherapy resistance in PI3K-mutated NSCLC.
- To investigate the efficacy of peptide-modified exosomes loaded with Ginsenoside Rb1 (Rb1@T-exo) in suppressing tumor growth and reversing immune resistance.
Main Methods:
- Tumor-derived exosomes (T-exo) were modified with TMTP1 peptide and loaded with Ginsenoside Rb1 (Rb1) via electroporation, creating Rb1@T-exo.
- In vitro and in vivo studies assessed tumor suppression, metastasis inhibition, signaling pathway modulation (PI3K/AKT/mTOR), immune microenvironment remodeling, and synergy with immune checkpoint blockade therapy.
- Transcriptomic and bioinformatic analyses identified key genes and pathways involved in resistance reversal.
Main Results:
- Rb1@T-exo demonstrated enhanced tumor targeting, stability, and bioavailability of Rb1.
- The treatment effectively suppressed tumor growth and metastasis, significantly inhibited the PI3K/AKT/mTOR pathway, and promoted M1 macrophage polarization and CD8+ T cell activity.
- Key pathways including PI3K/AKT/mTOR and PD-1/PD-L1 were identified as crucial for resistance reversal.
- Rb1@T-exo showed synergistic effects with immune checkpoint blockade therapy.
Conclusions:
- Peptide-modified Rb1@T-exo represents a promising targeted therapeutic platform for overcoming immunotherapy resistance in PI3K-mutated NSCLC.
- This approach offers a potential dual therapeutic strategy, addressing both tumor progression and immune evasion.
- The findings provide a strong foundation for future anti-tumor therapies targeting resistant cancers.
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